Alpha-synuclein is an abundant presynaptic protein. Point mutations in α-synuclein as well as α-synuclein gene duplications and triplications are associated with Parkinson's disease. (See, e.g., Polymeropoulos et al (1997) Science 276:2045-2047; Kruger et al (1998) Nat Genet 18:106-108; Zarranz et al (2004) Ann Neurol 55:164-173; Kiely et al (2013) Acta Neuropathol 125:753-769; Proukakis et al (2013) Neurology 80:1062-1064; Singleton et al (2003) Science 302:841; and Ibanez et al (2004) Lancet 364:1169-1171.) Additionally, α-synuclein is a major component of intracellular protein aggregates called Lewy bodies, which are pathological hallmarks of neurodegenerative disorders such as, for example, Parkinson's Disease, Lewy body disease, and multiple system atrophy. (See, e.g., Spillantini et al (1997) Nature 388:839-840; Wakabayashi et al (1997) Neurosci Lett 239:45-48; Arawaka et al (1998) Neurology 51:887-889; and Gai et al (1998) Lancet 352:547-548.)
Synucleinopathies comprise a class of neurodegenerative disorders; the term is used broadly to designate a spectrum of progressive degenerative disorders of the human nervous system. Misfolding and intracellular aggregation of α-synuclein are thought to be crucial factors in the pathogenesis of synucleinopathies that share, among other properties, the presence of abnormal α-synuclein immunoreactive inclusion bodies in neurons and/or macroglial cells. Synucleinopathies include, Parkinson's disease (PD), Parkinson's disease dementia (PDD), Lewy body disease (LBD), dementia with Lewy bodies (DLB), juvenile-onset generalized neuroaxonal dystrophy (Hallervorden-Spatz disease), multiple system atrophy (MSA), pure autonomic failure (PAF), and neurodegeneration with brain iron accumulation type-1 (NBIA-1).
Antibodies to α-synuclein and their use in, inter alia, therapeutic approaches to various synucleinopathies have been described previously. (See, e.g., International Patent Application Publication Nos: WO 1995/06407, WO 2004/041067, WO 2005/013889, WO 2005/047860, WO 2006/020581, WO 2006/045037, WO 2007/012061, WO 2008/103472, WO 2013/063516, WO 2013/112945, WO 2014/058924, WO 2010/069603, WO 2012/177972, WO 2013/066818, WO 2011/104696, WO 2009/133521, WO 2012/051498, WO 2011/107544, WO 2007/011907; see, e.g., Baba et al (1998) Am J Pathol 152:879-884; Emadi et al (2004) Biochemistry 43:2871-2878; Emadi et al (2007) J Mol Biol 368:1132-1144; Masliah et al (2005) Neuron 46:857-868.) However, the need remains for additional novel antibodies to α-synuclein for, inter alia, the effective treatment of synucleinopathies.